Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively
Abstract
To evaluate the inhibitory effects of trimethoprim and sulfamethoxazole on cytochrome P450 (P450) isoforms, selective marker reactions for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 were examined in human liver microsomes and recombinant CYP2C8 and CYP2C9. The in vivo drug interactions of trimethoprim and sulfamethoxazole were predicted in vitro using [I]/([I] + K(i)) values. With concentrations ranging from 5 to 100 microM, trimethoprim exhibited a selective inhibitory effect on CYP2C8-mediated paclitaxel 6alpha-hydroxylation in human liver microsomes and recombinant CYP2C8, with apparent IC(50) (K(i)) values of 54 microM (32 microM) and 75 microM, respectively. With concentrations ranging from 50 to 500 microM, sulfamethoxazole was a selective inhibitor of CYP2C9-mediated tolbutamide hydroxylation in human liver microsomes and recombinant CYP2C9, with apparent IC(50) (K(i)) values of 544 microM (271 microM) and 456 microM, respectively. With concentrations higher than 100 microM trimethoprim and 500 microM sulfamethoxazole, both drugs lost their selectivity for the P450 isoforms. Based on estimated total hepatic concentrations (or free plasma concentrations) of the drugs and the scaling model, one would expect in vivo in humans 80% (26%) and 13% (24%) inhibition of the metabolic clearance of CYP2C8 and CYP2C9 substrates by trimethoprim and sulfamethoxazole, respectively. In conclusion, trimethoprim and sulfamethoxazole can be used as selective inhibitors of CYP2C8 and CYP2C9 in in vitro studies. In humans, trimethoprim and sulfamethoxazole may inhibit the activities of CYP2C8 and CYP2C9, respectively.
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SMX acts as an inhibitor of CYP2C9.
“There may be a complex interplay between NA-SMX formation and CYP2C9 activity, as SMX has been shown to act as an inhibitor of CYP2C9.50”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [50]
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- Authors
- Wen, X., Wang, J.-S., Backman, J. T., Laitila, J., & Neuvonen, P. J.
- Affiliations
- University of Helsinki (FI)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 30
- Issue
- 6
- Pages
- 631-635
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2143225906
- Cited by
- 173
- References
- 25
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 6 · 2015: 7 · 2014: 12 · 2013: 7 · 2012: 6
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- trimethoprim, sulfamethoxazole, CYP2C8, CYP2C9, cytochrome P450 inhibition, drug-drug interactions, hepatic drug metabolism, sulfonamides, liver microsomes
- MeSH terms
- Anti-Infective Agents, Aryl Hydrocarbon Hydroxylases, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Enzyme Inhibitors, Female, Humans, Isoenzymes, Male, Microsomes, Liver, Recombinant Proteins, Steroid Hydroxylases, Sulfamethoxazole, Trimethoprim, Cytochrome P-450 CYP1A2, Steroid 16-alpha-Hydroxylase, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9, In Vitro Techniques
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